In September 2004, Amgen terminated their clinical trial of GDNF (glial cell line-derived neurotrophic factor) for Parkinson’s and banned its further use in humans. The GDNF protein was delivered to the brain through a catheter and was powered by a pump implanted into the abdomen. GDNF was considered one of the most promising treatments in the PD drug development pipeline and was expected to reach clinical use in a few years (2007 was mentioned). Patients from a Phase I open label trial reported great improvements, and they desperately wanted to continue their treatment. Other people with Parkinson’s (PWP), especially those in advanced stages, considered GDNF to be their best hope to stop the disease’s progression and to restore destroyed neurons. Our hopes were shattered when Amgen pulled the plug (and the pumps).

But looking back over the last ten years, I realize there also was a positive result. Although we didn’t know it at the time, on that day, a “parkinson’s movement” was born.

Part 1 of the “GDNF Saga” appeared in the April 2014 issue of ON THE MOVE—as part of a book review for “Monkeys in the Middle” (see issue 8 no.2, p. 39), and it related the many controversies swirling around the Phase II clinical trial, labeled as a failure. This article, Part 2, reviews the years from 2004-2014. How did GDNF advance from sitting unused in Amgen’s lab to currently being tested in two ongoing clinical trials, in the U.S. and the U.K?

Many PWP had been hopeful about GDNF being “the cure” or at least able to provide more effective and reliable treatment for PD symptoms. And perhaps it might even be neurotrophic and neuroregenerative. Many of us remember seeing Dr. Jeffrey Kordower’s videos of MPTP induced monkeys who received the GDNF infusions and appeared to be normal again. We met with trial participants who said they had gotten their lives and their smiles back with GDNF. Both of the earlier Phase I trials had positive results (1) , and most of the Phase II patients also were beginning to experience improvements, after about 6 months. But this fact could not be included in statistical analysis and based on the numbers, the Phase II trial did not meet its principle endpoints at 6 months, and was labeled a “failure.”

When questions about the possible presence of antibodies to GDNF and other safety issues were announced, many neuroscientists and biotechs lost interest in continuing GDNF research. Most of the trial participants were very willing to continue the treatment while research continued. The FDA approved of this plan, but Amgen refused to provide the GDNF. “It doesn’t work and it might be dangerous” they claimed. At the same time, they refused to release their patent for GDNF to other researchers and institutions even though offers were made.

But PWP, doctors and scientists, who still believed in the promise of GDNF didn’t let the issue die; it was too crucial for all of us. An advocacy group, “GDNF 4 Parkinson’s,” formed to uncover more information about the study, and the decision to halt clinical trials. For the first time, trial participants joined with PD grassroots advocates, trial doctors, researchers, and PD organizations (mainly the Parkinson’s Disease Foundation) to convince Amgen to release its hold on GDNF, and reinstate treatments for the current participants. The company refused to discuss GDNF with anyone until the study was published in a medical journal. That finally happened in March 2006­­­­—18 months after the trial halt. The toxicology report was not available until August 2007—3 years after the halt. There was very little opportunity to have a dialogue about these opposing viewpoints, and most people just moved on. But a small group kept the GDNF saga alive.

The long-awaited article in the Annals of Neurology stated that the Phase II clinical trial study failed to meet its primary endpoints, and there were possible safety issues—antibodies had formed in a few individuals. And there was evidence of cerebellum lesions in a few of the lab monkeys that had received the same kind of GDNF infusion(2). No adverse events were seen in the 100 people who had received GDNF in prior studies. When the tox report for the primate study was finally published, it offered little new information. The authors did advise the primate study sample was too small and they could not definitely conclude that GDNF caused lesions in the monkeys. They recommended additional primate studies. (3) In response, Dr. Michael Hutchinson, one of the Phase II trial doctors, reanalyzed the data and concluded that out of the 4 monkeys that had cerebellum lesions, all had received very high doses of GDNF which were then abruptly withdrawn.(4) The antibodies turned out not to be a problem. They occurred only in patients whose catheters became dislodged and subsided with no complications when the treatment ended.

Why were there such differing results between Phases I and II? Among those opposed to terminating the trial and benching GDNF, the main criticism was that there were too many differences in trial designs, such as the size of the dose, the pump /catheter systems, and the infusion methods, to allow meaningful comparison. The statistical analysis was also challenged—especially that the very small number of subjects may have caused the study to be underpowered and “thus incapable of ruling out a large effect of GDNF on Parkinson disease.” (5) So the GDNF did not fail, but the trial design and delivery methods did. The outcome of the study should be considered inconclusive, not negative.

To Amgen’s credit, over the past decade, they did supply GDNF for pre-clinical research, to address the safety issues and determine the best target area in the brain and the best way to deliver the right amount of the GDNF. I wasn’t expecting to find as much research as I did, but it is limited to animal studies. (6) They did set the stage for a renewal of clinical testing on humans.

The consensus now is that the putamen needs to be adequately covered for the GDNF to be successful. The delivery of the gene should be very precise and targeted. A number of methods of delivery are currently being studied and two are recruiting for clinical trials (see Clinical Trials below). Both trials will be using convection enhanced delivery (CED)—the use of pressurized infusions for safe, targeted, and homogeneous delivery of agents into small and large tissue. CED bypasses the blood–brain barrier, which has made it so difficult to deliver therapeutic agents into the brain right on target.

GDNF Clinical Trials

Ever since GDNF was banned in 2004, the return to clinical trials is something that many PWP have been reading about, talking about, planning for, working for, and always hoping that the trials will start soon. Currently there are two trials underway, and both are recruiting.

At the University of California, San Francisco, Dr. K. Bankiewicz has perfected surgical techniques for implanting genes precisely using “a novel interventional magnetic resonance imaging (MRI) targeting system to achieve precise , real time convection enhanced delivery.” (7) The Clinical trial is being housed at the NIH, and they are recruiting for the Phase I trial that started in May 2013.

Here are some of the comments about the NIH trial by 4 participants.

“Advocates have to practice what we preach and step up to the plate to volunteer. This is the one we have been waiting for nearly a decade so whatever the outcome it warrants the risk in this trial.”

“NIH wonderful facilities and excellent staff. It’s a shame that they haven’t attempted to draw on the experience of the trial participants about what in addition to GDNF is needed to heal from PD.”

“It’s a privilege to participate in a trial run by NIH. We all waited so long for some form of GDNF to be made available to patients in the form of a trial. I just consider myself to be lucky to qualify and participate at this time.”

“As a PWP who was a supporter of GDNF 4 Parkinson’s many years ago, I find myself wondering, where is the excitement in the PD community? Where are the volunteers for the trial?”

To learn more see: AAV2-GDNF for Advanced Parkinson’s Disease:

clinicaltrials.gov/ct2/show/NCT01621581?term=gdnf&rank=1

Across the pond in Bristol, UK, Dr. Steven Gill, funded by the Cure Parkinson’s Trust, developed a smaller and improved device that fits behind the ear where tiny plastic tubes are connected to a port in the brain. GDNF is infused through the port once a month, instead of the continuous delivery used in the earlier trials.

The Phase I has been completed and recruitment is underway for Phase II, which will be a placebo controlled double blind study. (8)

We don’t know the reason, but in 2008, (4 years after the trial halt) Amgen quietly transferred its license for the GDNF gene to Amsterdam Molecular Therapeutics (AMT), a small biotech company in the Netherlands, to be used for development of a gene therapy treatment for PD. The gene would be combined with AMT’s proprietary adeno-associated virus (AAV2) gene therapy platform.

In Jan. 2012, AMT was informed that the European Commission’s Standing Committee would not grant marketing authorization for Glybera, a therapy for treating lipoprotein lipase deficiency. More data was required. This was the company’s lead project, and AMT was running out of money.

More bad news for AMT. In Feb. 2012, Amsterdam Molecular Therapeutics “announced today that its board of directors is recommending a substantial corporate restructuring and financing transaction which, if approved by shareholders, will result in the assets and certain liabilities being acquired by a newly formed private company uniQure BV, also based in the Netherlands” (press release).

In March 2012, AMT was dissolved, and their business and operations went to uniQure.

“uniQure BV is a private company, also in the Netherlands created specifically for the Transaction. uniQure will act as the new holding company for the gene therapy business” (press release).

In June 2012, uniQure signed an agreement to partner with UCSF and the NIH on GDNF gene therapy for Parkinson’s.

In July 2013, Dr Krystof Bankiewicz, UCSF, was appointed chair of uniQure’s CNS Scientific Advisory Board.

The gene therapy developed by researchers at the University of California, San Francisco (UCSF), uses the GDNF gene, which uniQure (formerly Amsterdam Molecular Therapeutics) licensed from Amgen.

So the GDNF gene is now housed in uniQure. It seems like a good home. Hopefully, data and access to GDNF will be made available to other researchers. This is almost a model collaboration between an academic research center, a biotech and the NIH to cure Parkinson’s. All that is missing now is the voice of the patient.

Another surprise was the out licensing of Amgen’s GDNF protein to MedGenesis, a biotech in Canada. In January 2010, Medgenesis announced “that it has successfully entered into an agreement with Amgen granting MedGenesis an exclusive, worldwide license for glial cell line-derived neurotrophic factor (GDNF) protein in CNS and non-CNS indications…” subject to the rights of a co-exclusive licensee for CNS indications in certain countries…“As part of the license agreement, Amgen now holds a small equity stake in MedGenesis…”

“MedGenesis also granted BioVail, another Canadian biotech, license to its Convection Enhanced Delivery (CED) platform for use with GDNF in CNS indications. MedGenesis and Biovail will initially focus on the development of GDNF for Parkinson’s disease, …” (press release). In 2010 the Michael J Fox foundation awarded a grant of $2.1 million to MedGenesis Therapeutix Inc., and Biovail Laboratories International SRL to further their collaboration in the development of GDNF, referred to as “a first in class disease modifying agent.”

This article is both a history of the GDNF clinical trials and a personal account of a grassroots campaign to reinstate GDNF clinical trials and research. I have been following the development of GDNF since the trial halt in 2004. GDNF 4 Parkinson, was formed very soon after to uncover more information about the study, and the decision to halt clinical trials. For the first time, trial participants joined with PD grassroots advocates, trial doctors, researchers and PD organizations (mainly the Parkinson’s Disease Foundation) to convince Amgen to release its hold on GDNF, and reinstate treatments for the current participants. Patients, doctors and scientists from all over joined together both in person and online to support the trial participants’ appeal for compassionate use to reinstate their treatments.

The lives of every PWP would be affected by Amgen’s decision. If it had been allowed research to continue, who knows where we would be today? The animal research that was allowed during this period surely perfected the delivery methods that are now being used, but it took four years before Amgen granted license to another biotech. It took 8 years for the first new GDNF trials to start up. That’s a long time for a PWP.

GDNF 4 Parkinsons failed to achieve a change in Amgen’s policy, but if not for our advocacy, GDNF probably would not been given another chance.

What we learned

Research should be patient-centered.

Patients should be a part of the research team at every level .

We need objective measures of symptoms that will consider the variability of symptoms between individuals and within each individual depending on the time of day, activity level and emotional state. Incorporate these into trial design and evaluation of statistical data.

Researchers should share data with other scientists. Completed studies should be available on the web immediately, before the journal article appears in print.

The informed consent should include an understandable explanation of why or why not trial participants will have access to the experimental treatments that work well for them. Patients in a Phase 2 or 3 trial who were in the control group, should be offered treatment at the end of the trial, if they want it.

Benefit /risk decisions should be made by the patients.

If everyone in the Parkinson’s community works together to fight PD, we might really see the cure in 5 years.